Project Abstract Human Immunodeficiency Virus (HIV-1) remains one of the leading causes of death worldwide principally from developing countries. The present combined Antiretroviral Therapy (cART) has significantly reduced disease mortality among patients. However, major limitations in this treatment are the complexity of dosing regimens, drug metabolism, and numerous side effects. Furthermore, most of the cART drugs have limited penetrance into viral reservoir cells in the brain tissue. Delivering therapeutic agents to the brain remains a major challenge primarily due to the ineffective transmigration of drugs through Blood Brain Barrier (BBB). Therefore, the advent of nanomedicine-based drug delivery has stimulated the development of innovative systems for drug delivery. However, it resulted in limited success because of the biocompatibility, sustainability, and toxicity of the formulation itself. In this regard, nanodiamond (ND) has established an excellent drug carrier molecule for drug delivery application. ND is a chemically synthesized diamond-shaped carbon nanoparticle (~ 5nm) with the large accessible surface for drug binding. More importantly, the natural biocompatibility and the non-toxic nature of the ND make it a more efficient drug carrier molecule than any other carbon-based carrier molecules. Considering the next-generation therapy for HIV is one of priority research areas of Office of AIDS Research, the present project proposes to develop a nanodiamond-based anti- HIV nano drug molecule that will be conjugated with the microglia-specific antibody (Tmem119) for targeted drug delivery to the brain. The proposed nanodrug can be used to directly deliver an anti-HIV drug to specifically inflammatory areas of the brain where most of the infected microglia and the virus are present. We hypothesize that nanodiamond mediated drug delivery will be more efficient, safe and effective than conventional drugs. Being an R15 AREA grant proposal, this cutting-edge drug delivery research will also help to stimulate the research environment at our leading minority-serving institution and also encourage our current undergraduate/graduate students to expose to the biomedical research environment.